Adenosine is a compound that executes various physiological functions through specific receptors in cell membranes. Extracellular adenosine acts as a neurotransmitter in a variety of physiological systems. In general, adenosine counterbalances excessive activities of a given organ and thereby provides protection from the harmful effect of stress (Jacobson, K. A. et al.; J. Med. Chem., 35, pp. 407–422, 1992). This is a partially formed negative feedback loop in an attempt to decrease the cellular energy demand by adenosine formed via decomposition of endocellular and extracellular ATP (adenosine triphosphate) and to increase oxygen supply. Adenosine is important in maintaining the normality of essential organs such as the brain, heart and kidney. For example, it was proved that the injection of an adenosine agonist into the brain has a neuroprotective effect, and it is also known to be related to pain, intelligence, movement, and sleep.
Adenosine receptors have been classified as P1 and P2 receptors through pharmacological study and molecular cloning. Adenosine acts as a substrate for P1 receptors whereas ATP, ADP, UTP, and UDP act as substrates for P2 receptors to manifest physiological activity. Among these, four different subtypes of adenosine receptors were identified for P1 receptors, which were classified as A1, A2, or A3 based on the ligand affinity, distribution in the system, and functional process. A2 is again divided into A2a and A2b. These adenosine receptors form one class of G-protein-coupled receptors. The adenosine A1, A2a and A2b receptors were pharmacologically identified using various selective ligands. However, the adenosine A3 receptor was first identified in 1992 (Zhou, Q. Y. et al.; Proc. Natl. Acad. Sci. USA, 89, pp. 7432–7436, 1992). Numerous studies are being carried out to identify the particular physiological function of this receptor.
Adenosine A1 and A2 receptor agonists are usually antihypertensives, antipsychotic, anti-arrhythmia drugs, and fat metabolism inhibitors (diabetes treatment drugs), and neuroprotective drugs, which have been studied quite well. Antagonists are xanthine derivatives or compounds wherein various heterocycles are fused together, which have been developed for anti-asthmatics, antidepressants, anti-arrhythmia drugs, renal protection drugs, anti-Parkinson's drugs, and nootropics. However, recently commercialized drugs are adenosine itself for treatment of supraventricular tachycardia, and the adenosine transfer inhibiting drug, dipyridamole, which is being used as a supplemental drug for warfarin in preventing blood coagulation after heart surgery. Such development has been unsuccessful because adenosine receptors are present all over the system, and there are various concomitant pharmacological effects until the receptor is activated, and therefore no compound can activate only the adenosine receptor.
Among the adenosine receptors, the A3 adenosine receptor has recently been identified as unlike the widely known A1 and A2 adenosine receptors, and therefore its role has not yet been elucidated. Various studies are in progress for development of selective ligands for the A3 adenosine receptor. For pharmacological study on the adenosine A3 receptor, three radiolabeled ligands such as [125I]ABA (N6-(4-amino-3-125I [iodo]benzyl)adenosine), [125I]APNEA ([125I]N6-2-(4-aminophenyl)ethyl adenosine) or [125I]AB-MECA ([125I]4-aminobenzyl-5′-N-methylcarboxyamidoadenosine) are being employed. When A3 adenosine receptor was expressed in Chinese hamster ovary (CHO) cells, it had an inhibiting effect on adenylyl cyclase, the enzyme that produces cAMP from ATP. When the A3 adenosine receptor was activated by an agonist, it was proved that phosphatidyl inositol decomposed to activate GTP-dependent phospholipase C (guanosine triphosphate-dependent phospholipase), the enzyme that produces inositol phosphate and DAG (Ramkumar, V., et al.; J. Biol. Chem., 268, pp. 168871–168890, 1993: Abbracchio, M. P. et al.; Mol. Pharmacol., 48, pp. 1038–1045, 1995). This discovery explains the potential response pathway by A3 adenosine receptor activation for cerebral ischemia because this secondary transmitter system means the response pathway of nerve damage in brain ischemia. In addition, the adenosine A3 agonist has a protective effect against brain diseases like epilepsy, and a protective effect for the heart. Activation of the A3 adenosine receptor results in the emission of inflammation-inducing factor like histamine from mast cells, and contracts organs. High concentrations of agonist or antagonist may result in apoptosis in immune cells. An agonist of A3 adenosine receptors inhibits the generation of tumor necrosis factor (TNF-α), which is the inflammation transmitter, and also inhibits the formation of MIP-1α, interleukin-12, and interferon-γ, which are inflammation mediators. Therefore, A3 adenosine antagonists have the potential for development as anti-inflammatories and antiasthmatics. The foregoing shows that there exists need for highly A3 selective adenosine receptor agonists.
Among the compounds that have been developed and studied so far, N6-(3-iodobenzyl)-5′-(N-methylcarbamoyl)adenosine (IB-MECA) which is shown in the following Structure 1, and N6-(3-iodobenzyl)-2-chloro-5′-(N-methylcarbamoyl)adenosine (Cl-IB-MECA) shown in Structure 2 are representative selective adenosine A3 ligands which showed high selectivity for A3 adenosine receptors over A1 and A2 adenosine receptors.

The invention provides highly selective A3 adenosine receptor agonists and antagonists. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.